Propofol composition

ABSTRACT

The present invention is directed to a sterile pharmaceutical composition comprising a propofol containing oil-in-water emulsion formulation having as an antimicrobial agent, a member selected from the group consisting of benzyl alcohol and ethylene diamine tetra acetic acid; benzethonium chloride; and benzyl alcohol and sodium benzoate.

FIELD OF THE INVENTION

The present Invention relates to pharmaceutical compositions containing2,6-diisopropylphenol.

BACKGROUND OF THE INVENTION

Propofol (26-diisopropylphenol) an injectable anesthetic which hashypnotic properties and can be used to induce and maintain generalanesthesia and for sedation. Injectable anesthetics such as propofol areadministered directly into the bloodstream. This results in a rapidonset of anesthesia influenced almost entirely by the rate at which theanesthetic agent crosses the blood-brain barrier. Therefore, theanesthetic agent must have sufficient lipid solubility to be able tocross this barrier and depress the relevant mechanisms of the brain.Propofol is poorly water soluble and therefore is generally formulatedas an emulsion. Propofol containing emulsions have been shown to supportmicrobial growth. Therefore it is desirable to formulate propofolemulsions in a manner in which microbial growth is prevented. EDTA(ethylene diamine tetraacetic acid) has been shown to delay, but notprevent, the onset of microbial growth in propofol emulsions. See U.S.Pat. No. 5,714,520.

Accordingly it is an object of the present invention to provide apropofol containing pharmaceutical composition that providesantimicrobial benefits above that found in existing compositions and/orprevents the onset of microbial growth in such compositions.

SUMMARY OF THE INVENTION

The present invention is directed to a sterile pharmaceuticalcomposition comprising a propofol containing oil-in-water emulsionformulation having as an antimicrobial agent, a member selected from thegroup consisting of benzyl alcohol and ethylene diamine tetraaceticacid; benzethonium chloride; and benzyl alcohol and sodium benzoate.

DETAILED DESCRIPTION OF THE INVENTION

The term "anti-microbial" means an agent which delays onset or retardsrate of growth to less than 1 logarithmic increase over a 24 hour periodas compared to an unpreserved formulation.

The composition of the present invention comprises an oil in wateremulsion in which the 2,6-diisopropylphenol, either alone or dissolvedin a water immiscible solvent, for example a vegetable oil, isemulsified with water by means of surfactant.

Typically the solvent is an oil such as soy bean oil, safflower oil,cottonseed oil, corn oil, sunflower oil, arachis oil, castor oil, orolive oil. Preferably the oil is soybean oil. Alternatively the solventcan be an ester of a medium or long chain fatty acid, for example amono-,di-, or triglyceride; or a compound such as ethyl oleate,isopropyl myristate, isopropyl palmirate, a glycerol ester or a polyoxylhydrogenated castor oil. Other suitable solvents may be marine oils, forexample cod liver or other fish derived oils, or fractionated oils, suchas fractionated coconut oil or modified soybean oil. The composition ofpresent invention may also comprise a mixture of two or more of theabove water immiscible solvents.

The 2,6-diisopropylphenol, either alone or dissolved in the waterimmiscible solvent, is emulsified with the aid of a surfactant. Suitablesurfactants include synthetic non-ionic surfactants, for exampleethoxylated ethers and esters and polypropylene polyethylene blockcopolymers, and phosphatides, as for example egg and soy phosphatides.Preferably, the surfactant is egg phosphatide.

Preferred compositions of the present invention comprise from 0.1 to5.0% by weight, preferably 1 to 2% by weight, and most preferably 2% byweight of 2,6-diisopropylphenol; from to 2 to 30% by weight, preferably10 to 20% by weight of a nonionic surfactant; from 2 to 90% by weight ofa water immiscible solvent, and the balance of the composition beingwater.

The antimicrobial systems utilized in the compositions of the presentinvention are selected from the group consisting of benzyl alcohol andethylene diamine tetraacetic acid; benzethonium chloride; and bcnzylalcohol and sodium benzoate. The concentration of the antimicrobialagents in the final composition will vary depending on the particularagent or agents selected. For instance in a preferred composition of theinvention the amount of benzyl alcohol is in the range of about 0.0175%to 0.9% (w/v), more preferably about 0.07% to about 0.45%, mostpreferred in the range of 0.15%. In an alternate preferred compositionof the invention, the amount of benzyl alcohol is about 0.07% to about0.9%, optionally including an amount of EDTA of about 0.005%. Yetanother embodiment provides a composition including an amount ofbenzethonium chloride of about 0.1% to about 0.1%. Optionally, thecomposition of the present invention include 0.07% nb. The mostpreferred compositions of the present invention include bcnzyl alcoholand nb. The compositions of the present invention may be prepared byconventional processes as for example that disclosed in U.S. Pat. No.5,714,520.

The compositions of the present invention can also contain pH adjustingagents such as sodium hydroxide so they can be formulated at aphysiologically neutral pH.

The compositions of the present invention may also be made isotonic bythe incorporation of a suitable additive such as glycerol.

A particularly preferred composition of the present invention is as setforth below.

                  TABLE 1                                                         ______________________________________                                        (weight percent)                                                                             Broad      Preferred                                                                            Particularly Preferred                         Component              Range          Range         Amount                  ______________________________________                                        2,6-       0.1-5.0    1.0-2.0  1.0                                              diisopropylphenol                                                             Soybean Oil             1-30        10-30       10                            Egg Phosphatide        0.2-2.0     0.7-2.0    1.2                             Benzyl alcohol         0.0175-0.9    0.07-0.45  0.15                          nb                     0.07           0.07          0.07                      Glycerol                                            2.25                      Sodium Hydroxide       q.s.           q.s.          q.s.                      Water for Injection    to 100         to 100        to 100                  ______________________________________                                    

The compositions of the present invention may be used for the inductionof anesthesia prior to maintenance with a conventional inhalationanesthetic or they may used as a sole anesthetic agent for shortduration or by repeated administration or by continuous infusion theymay be use as a sole anesthetic agent of longer duration.

The invention is illustrated by the following representative examples:

EXAMPLE 1

The compositions of the present invention may be formulated followingprocedures well known to those skilled in the art. Specific reference ismade to U.S. Pat. No. 5,714,520 which is hereby incorporated byreference.

EXAMPLE 2

Solutions of 0.45% benzyl alcohol/0.005% EDTA, 0.035%benzylalcohol/0.005% EDTA, 0.45% benzyl alcohol/0.07%nb, and 0.35% benzylalcohol/0.07%nb were passed through a 0.45 micron filter and tested bythe USP 23 preservative effectiveness test as described in United StatesPharmacopoeia 23-NF 18, 1995 Ed., Chapter 51, which is incorporatedherein by reference. Briefly, this involves inoculating the testsolution with 10⁵ to 10⁶ test organisms per milliliter and thendetermining the number of surviving organisms after 7, 14, 21, and 28days incubation at 20-25° C. using standard microbiological methods. Day0 data is not required by USP 23 but was included in this study. Afiltration and was method was used to remove the inactivating agents forpurposes of recovering the microorganisms, but other equivalent methodscan also be validated for use. The USP test organisms include thebacteria Staphylococcus aureus, Escherichia coli, and Pseudomonoasaeruginosa, a yeast (Candida albicans), and a mold (Aspergillus niger).In order to meet the criteria of the USP 23 preservative effectivenesstest, the bacteria must demonstrate a 90% (1 logarithmic) reduction atDay 7 and a 99.9% reduction (3 logarithmic) reduction at Day 14 from theinitial inoculum level. The initial inoculum level can either becalculated knowing the stock culture concentration or by using a buffercontrol instead of the test solution. The results, using formulationswhich are 10% fat emulsions, are given below in Tables 2 through 5 wherethe number reported in the number of organisms pre milliliter. ND meansnot detected, i.e., below the levels of detection by the assay.

                  TABLE 2                                                         ______________________________________                                        (0.45% benzyl alcohol/0.005% EDTA)                                                   Organism                                                               Time   A. niger                                                                              C. albicans                                                                             E. coli                                                                             P. aeruginosa                                                                          S. aureus                             ______________________________________                                        Inoculum                                                                             390,000 440,000   750,000                                                                             460,000  610,000                                 per ml                                                                        product                                                                       0 Hr.       300,000    300          <10     <10          <10                                                      ND         ND              ND                                                    Day 7       210,000    340,000                                                  680        3,000                                                           47,000                                  Day 14      210,000    350,000      190        200             7,200                                                 Day 21      3,400      270,000                                                  40         60                                                              4,300                                   Day 28      130        105,000      10         10              1,020        ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        (0.035% BENZYL ALCOHOL/0.005 EDTA)                                                   Organism                                                               Time   A. niger                                                                              C. albicans                                                                             E. coli                                                                             P. aeruginosa                                                                          S. aureus                             ______________________________________                                        Inoculum                                                                             390,000 440,000   750,000                                                                             460,000  610,000                                 per ml                                                                        product                                                                       0 Hr.      300,000     310,000      360,000    310,000         430,000                                               Day 7      300,000     330,000                                                  40         105,000                                                         36,000                                  Day 14     210,000     310,000      <10     68,000          3,500                                                      ND                                   Day 21     120,000     320,000      <10     67,000          740                                                        ND                                   Day 28     29,000      110,000      >10     38,000          170                                                        ND                                 ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        (0.45 benzyl alcohol/0.07 nb)                                                        Organism                                                               Time   A. niger                                                                              C. albicans                                                                             E. coli                                                                             P. aeruginosa                                                                          S. aureus                             ______________________________________                                        Inoculum                                                                             390,000 440,000   750,000                                                                             460,000  610,000                                 per ml                                                                        product                                                                       0 Hr.       260,000    340,000       380,000   440,000         390,000                                               Day 7       260,000    390,000                                                   86,000    101,000                                                         30,000                                  Day 14      29,000     350,000       62,000    14,900          1,350                                                 Day 2l      22,000     203,000                                                   80,000    2,800           100       Day 28      290        87,000        76,000    150             10           ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        (0.035 BA/0.07% NB)                                                                 Organism                                                                Time  A. niger                                                                              C. albicans                                                                             E. coli                                                                              P. aeruginosa                                                                          S. aureus                             ______________________________________                                        In-   390,000 440,000   750,000                                                                              460,000  610,000                                 oculum                                                                        per ml                                                                        product                                                                       0 Hr.       370,000    450,000       420,000   550,000         520,000                                               Day 7       250,000    530,000                                                   8,800,000 3,500,000                                                       310,000                                 Day 14      130,000    410,000       7,100,000 3,400,000       92,000                                                Day 21      41,000     440,000                                                   5,800,000 30,000                                                          49,000                                  Day 28      13,000     300,000       2,180,000 7,000           22,100       ______________________________________                                    

EXAMPLE 3

The antimicrobial properties of various Propofol formulations weredetermined by a spiked hold time study. Briefly, a Propofol formulationis inoculated to achieve approximately 100 organisms per 10 mL sample.The organisms used include Staphylococcus aureus, Pseudomonasaeruginosa, Escherichia coli, Candida albicans, Bacillus subtilis,Aspergillus niger, and Clostridium sporogenes. The inoculated samplesare held for various times and then filtered in duplicate. The filtersare washed with buffer and then placed on appropriate agar growth media.The antimicrobial agents should reduce the growth rate such that thereis less than a 1 logarithm increase within a 24 hour period.

C. albicans presented the most resistance to the preservative system.The C. albicans results from the spiked hold time study are shown belowfor various propofol formulations. E. coli, P. aeruginosa, and B.subtilis also demonstrated some resistance to the antimicrobial agents(data not shown). The remaining test organisms increased less than2-fold over the 7 day test period. The results are shown in cfu/mL. Avalue of >300indicates too numerous to count; these data points maystill meet the acceptance criteria of less than 1 logaritmic increase.In the Tables, BA=Benzyl Alcohol, NB=Sodium Benzoate. The percent ofbenzyl alcohol is indicated in w/v for each formulation. The percentsSodium benzoate, when present, is 0.07% (w/v).

    ______________________________________                                        Formulation                                                                             0 hours 1 24 hours  48 hours 1                                                                            7 days 1                                ______________________________________                                        0.45 BA/NB                                                                              37        35        28      56                                        0.15 BA only      59           102          >300     >300                     0.15 BA/NB        59           45           >300     >300                     0.13 BA/NB        66           57           >300     >300                     0.10 BA/NB        53           59           >300     >300                     0.07 BA/NB        34           120          >300     >300                     0.035 BA/NB       33           125          >300     >300                     0.0175 BA/NB      38           185          >300     >300                   ______________________________________                                    

What is claimed is:
 1. A sterile oil-in-water emulsion pharmaceuticalcomposition comprising:from 0.1 to 5.0 weight percent propofol; from 2.0to 30 weight percent solvent; from 0.2 to 2.0 weight percent surfactant;2.25 weight percent glycerol; from 0.0175 to 0.9 weight percent ofbenzyl alcohol alone or in combination with sodium benzoate as anantimicrobial agent and the balance of the composition being water. 2.The composition of claim 1 havingfrom 1.0 to 2.0 weight percentpropofol; from 1.0 to 30 weight percent solvent; from 0.7 to 2.0 weightpercent surfactant; from 0.07 to 0.45 weight percent benzyl alcohol;and, 0.07 weight percent sodium benzoate.
 3. The composition of claim 2having1.0 weight percent propofol; 10 weight percent solvent; 1.2 weightpercent surfactant; 0.15 weight percent benzyl alcohol; and, 0.07 weightpercent sodium benzoate.
 4. The composition according to claim 1 whereinthe propofol is emulsified by means of a surfactant.
 5. The compositionaccording to claim 4 wherein the surfactant is an ethoxylated ether orester, a polypropylene polyethylene block copolymer or a phosphatide. 6.The composition according to claim 5 wherein the surfactant is eggphosphatide.
 7. The composition according to claim 1 wherein thepropofol is dissolved in a water-immiscible solvent.
 8. The compositionaccording to claim 7 wherein the solvent is soybean oil, safflower oil,cottonseed oil, corn oil, sunflower oil, arachis oil, castor oil orolive oil.
 9. The composition of claim 4 wherein the solvent is soybeanoil.
 10. The composition of claim 1 wherein sodium benzoate is incombination with benzyl alcohol.
 11. The composition according to claim10 wherein the propofol is emulsified by means of a surfactant.
 12. Thecomposition according to claim 11 wherein the surfactant is anethoxylated ether or ester, a polypropylene polyethylene block copolymeror a phosphatide.
 13. The composition according to claim 12 wherein thesurfactant is egg phosphatide.
 14. The composition according to claim 10wherein the propofol is dissolved in a water-immiscible solvent.
 15. Thecomposition according to claim 14 wherein the solvent is soybean oil,safflower oil, cottonseed oil, corn oil, sunflower oil, arachis oil,castor oil or olive oil.
 16. The composition according to claim 15wherein the solvent is soybean oil.
 17. A method of inducing anesthesiaor sedation comprising administering to a patient in need thereof ananesthesia- or sedation-inducing amount of a sterile pharmaceuticalcomposition comprising a propofol containing oil-in-water emulsionhaving as an antimicrobial agent benzyl alcohol alone or in combinationwith sodium benzoate.
 18. A method of maintaining anesthesia or sedationcomprising administering to a patient in need thereof an anesthesia- orsedation- maintaining amount of a sterile pharmaceutical compositioncomprising a propofol containing oil-in-water emulsion having as anantimicrobial agent benzyl alcohol alone or in combination with sodiumbenzoate.
 19. A method of inducing anesthesia or sedation comprisingadministering to a patient in need thereof an anesthetic or sedationinducing amount of a sterile oil-in-water emulsion pharmaceuticalcomposition comprising:from 0.1 to 5.0 weight percent propofol; from 2.0to 30 weight percent solvent; from 0.2 to 2.0 weight percent surfactant;from 2.0 to 3.0 weight percent glycerol; from 0.0175 to 0.9 weightpercent of benzyl alcohol and sodium benzoate as an antimicrobial agent;and the balance of the composition being water.
 20. The method of claim19 wherein the pharmaceutical composition is1.0 weight percent propofol;10 weight percent solvent; 1.2 weight percent surfactant; 0.15 weightpercent benzyl alcohol; and, 0.07 weight percent sodium benzoate. 21.The method of claim 20 wherein the solvent is soybean oil and thesurfactant is egg phosphatide.
 22. A method of maintaining anesthesia orsedation comprising administering to a patient in need thereof ananesthesia- or sedation- maintaining amount of a sterile oil-in-wateremulsion pharmaceutical composition comprising:from 0.1 to 5.0 weightpercent propofol; from 2.0 to 30 weight percent solvent; from 0.2 to 2.0weight percent surfactant; from 2.0 to 3.0 weight percent glycerol; from0.0175 to 0.9 weight percent of benzyl alcohol and sodium benzoate as anantimicrobial agent; and the balance of the composition being water. 23.The method of claim 22 wherein the pharmaceutical composition is1.0weight percent propofol; 10 weight percent solvent; 1.2 weight percentsurfactant; 0.15 weight percent benzyl alcohol; and, 0.07 weight percentsodium benzoate.
 24. The method of claim 23 wherein the solvent issoybean oil and the surfactant is egg phosphatide.